Tocilizumab Appears Safe and Effective in Treating Rheumatoid Arthritis

Newswise — Phase III testing shows that a potential new therapy called tocilizumab is safe and effective in the treatment of rheumatoid arthritis, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Boston, Mass.

Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 2.1 million Americans have RA, most of them women.

Researchers tested the effectiveness and safety of tocilizumab, a new humanized, anti-human IL-6 receptor antibody, in patients with moderate to severe active RA despite being treated with methotrexate. Tocilizumab blocks the function of interleukin-6, a molecule that plays a fundamental role in maintaining the inflammation that affects patients with RA.

623 participants in this double-blind, placebo-controlled, phase three trial were randomly given 8 mg/kg of tocilizumab, 4 mg/kg of tocilizumab, or placebo intravenously every four weeks for twenty-four weeks. All participants received weekly doses of methotrexate throughout the study. No other disease-modifying anti-rheumatic drugs, or DMARDS, were allowed.

Researchers found that a significantly higher proportion of patients treated with tocilizumab showed improvements in the primary endpoint (ACR 20 at 24 weeks). The ACR 20 response was achieved by 59 and 48 percent of patients receiving tocilizumab at 8 and 4mg/kg, respectively, compared to 27 percent on placebo. The more stringent ACR 70 response was achieved by 22 percent of patients treated with 8mg/kg tocilizumab, but only two percent of patients receiving placebo.

The ACR 20/50/70 scoring criteria measures improvement in tender and swollen joint count and improvement in at least three of the following five criteria: pain; level of disability; overall self-assessment; overall physician assessment; and level of acute phase reactants (including the C-reactive protein or sedimentation rate).

Adverse events were similar across all groups of participants. Of 41 serious adverse events affecting approximately six percent of participants in each group, 15 were considered related to the study treatment and 11 led to discontinuation of treatment. Serious infections were observed more often in the participants treated with tocilizumab than the placebo group (2.9 percent in the 8 mg/kg group, 1.4 percent in the 4 mg/kg group, and 1 percent in the placebo group).

"The data prove that IL-6 is importantly involved in the inflammatory response of RA, and that targeting the IL-6 receptor with tocilizumab is a useful novel treatment modality," said Josef Smolen, MD; professor of medicine; chairman, department of internal Medicine III and division of rheumatology; Medical University of Vienna; Chairman, 2nd department of medicine, Hietzing Hospital; Vienna, Austria; and an investigator in the study.

The ACR is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with or at risk for arthritis and rheumatic and musculoskeletal diseases. http://www.rheumatology.org/annual

Editor's Notes: Andre Beaulieu, MD, will present this research during the ACR Annual Scientific Meeting at the Boston Convention and Exhibition Center from 2:30 " 4:30 pm ET on Saturday, November 10, 2007, in Grand Ballroom East. Dr. Joseph Smolen will be available for media questions and briefing at 8:30 am ET on Saturday, November 10 in the on-site press conference room, Room 251. Presentation Number: 2089

Targeted Inhibition of the IL-6 Receptor with Tocilizumab Effectively Reduces Disease Activity in Patients with Rheumatoid Arthritis

Andre D. Beaulieu1, Andrea Rubbert-Roth2, Thasia Woodworth3, Emma Alecock3, Rieke Alten4, Josef Smolen5. 1Laval University, Quebec, QC, Canada; 2Medical Clinic I, University of Cologne, Cologne, Germany; 3Roche Products Ltd, Welwyn, United Kingdom; 4Schlosspark Clinic, University Medicine Berlin, Berlin, Germany; 5Medical University of Vienna and Hietzing Hospital, Vienna, Austria

Purpose: Interleukin (IL)-6 is central to the regulation of chronic inflammation and is implicated in the pathogenesis of rheumatoid arthritis (RA). An emerging therapeutic approach for RA treatment is targeted inhibition of IL-6 signaling. The aim of this study was to test the efficacy and safety of tocilizumab (TCZ), a novel humanized anti-human IL-6 receptor antibody, in patients with moderate to severe active RA despite treatment with methotrexate (MTX).

Methods: 623 patients were evaluated in this randomized, double blind, placebo controlled phase 3 trial. Patients received either 8 mg/kg TCZ, 4 mg/kg TCZ, or placebo intravenously every 4 weeks. All groups received MTX at stable pre-study doses (10-25 mg weekly) throughout the study. No other disease-modifying anti-rheumatic drugs (DMARDs) were allowed.

Results: A significantly higher proportion of TCZ-treated patients showed improvements in the primary endpoint, ACR20 at 24 weeks (TCZ 8 mg/kg 59%; TCZ 4 mg/kg 48%; placebo 27%; p<0.0001). Significantly more patients also achieved ACR50 and ACR70 response by 24 weeks with TCZ 8 mg/kg and TCZ 4 mg/kg vs. placebo (ACR50: 44% and 32% vs. 11%, respectively; ACR70: 22% and 12% vs. 2%, respectively, p <0.0001). A total of 21 patients achieved ACR90 response, 11 (5.4%) with TCZ 8 mg/kg and 10 (4.7%) with TCZ 4 mg/kg vs. none for placebo. Significant improvements in all ACR core set parameters were observed with TCZ 8 mg/kg and 4 mg/kg vs. placebo, with highly significant differences (p <0.0001) for many components (TJC, SJC, ESR with TCZ 4 mg/kg; TJC, SJC, patient's global assessment of disease activity, patient's assessment of pain, ESR and CRP with TCZ 8 mg/kg). In keeping with TCZ's effects on the IL-6-regulated production of acute phase reactants, CRP levels dropped to normal at 2 weeks' treatment with 8 mg/kg TCZ and remained normal to study end. A similar overall frequency of adverse events (AEs) was reported in all groups. Of 41 serious AEs affecting approximately 6% of patients in each group, 15 were considered related to study treatment and 11 led to discontinuation of treatment. Serious infections were observed with a higher frequency in patients treated with TCZ (2.9% in the TCZ 8 mg/kg group, 1.4% in the TCZ 4 mg/kg group and 1% in the placebo group).

Conclusions: This large phase 3 study provides evidence that IL-6 plays a fundamental role in maintaining the inflammation that drives RA. Inhibition of the IL-6 receptor and the subsequent signaling cascade with TCZ improves the signs and symptoms of RA significantly, with a good safety and tolerability profile.

Disclosure Block: J. Smolen, Clinical Department of Rheumatology University Clinic for Internal Medicine I, Vienna, Austria, 3; F Hoffmann La Roche, 5.